tbuckley/cabot-search huggingface dataset:
Fire-eater's lung
Authors: PE Brander, E Taskinen, B Stenius-Aarniala
Journal: European Respiratory Journal (1992)

Acute pneumonitis following aspiration of petroleum products is usually related to accidental poisonings in children. We describe here two cases of hydrocarbon pneumonitis in fire-eaters, caused by accidental aspiration of petroleum during the performance of fire-eating. Both patients had cough, dyspnoea, chest pain and fever. Chest X-rays showed basal lung infiltrates and, 2 weeks later, pneumatocele formations. Reversible bronchial hyperresponsiveness and restrictive ventilatory limitation were demonstrated in one of the patients. The bronchoalveolar lavage specimen showed cytoplasmic vacuolation of the macrophages and neutrophilia. After treatment with antibiotics and corticosteroids the symptoms disappeared and the lung function values returned to normal within 2-3 weeks. Radiological resolution of the pneumatoceles occurred within 2-12 months.
Abstract P3005: Cannabinoid Receptor 1 Antagonist Genistein Attenuates Marijuana-Induced Vascular Inflammation
Authors: Mark Chandy, Tzu-tang T Wei, Masataka Nishiga, Angela Zhang, Kaavya K Kumar, Dilip Thomas, Amit Manhas, Siyeon Rhee, Johanne M Justesen, Ian Y Chen, Hung-Ta Wo, Johnson Y Yang, Saereh Khanamiri, Frederick Seidl, Noah Burns, Chun Liu, Nazish Sayed, Jiun-Jie Shie, Chih Fan Yeh, Kai-chien YANG, Edward Lau, Kara Lynch, Manuel Rivas, Brian Kobilka, Joseph C Wu
Journal: Circulation Research (2022)

Epidemiological studies reveal that marijuana increases the risk of cardiovascular disease (CVD); however, little is known about the mechanism. Δ 9 -tetrahydrocannabinol (Δ 9 -THC), the psychoactive component of marijuana, binds cannabinoid receptor 1 (CB1/CNR1) in the vasculature and is implicated in CVD. A UK Biobank analysis found that cannabis is an independent risk factor for CVD. We found that marijuana smoking activated inflammatory cytokines implicated in CVD. In silico virtual screening identified genistein, a soybean isoflavone, as a putative CB1 antagonist. Human-induced pluripotent stem cell-derived endothelial cells (hiPSC-ECs) were used to model Δ 9 -THC induced inflammation and oxidative stress via NF-κB signaling. Knockdown of the CB1 receptor with siRNA, CRISPR interference (CRISPRi), and genistein attenuate the effects of Δ 9 -THC. In mice, genistein blocked Δ 9 -THC-induced endothelial dysfunction in wire myograph, reduced atherosclerotic plaque, and had minimal penetration of the central nervous system (CNS). Genistein is a peripherally restricted CB1 antagonist that attenuates Δ 9 -THC-induced atherosclerosis.
Abstract P1017: Tissue Engineered Human Acellular Blood Vessels For Coronary Artery Bypass Grafting
Authors: Adam R Williams, Joseph Nellis, Zachary Wegermann, Sharon McCartney, Mihai V Podgoreanu, Sachin Mehta, Kyha D Williams, Melissa A Daubert, Robert Kirkton, Kevin Nash, Laura Niklason, Jeffrey H Lawson, Alan P Kypson
Journal: Circulation Research (2022)

Objective: Conduit for coronary artery bypass grafting (CABG) can be limited due to poor quality or prior removal of saphenous veins. A human acellular vessel (HAV) bioengineered from vascular cells and then decellularized for implantation may provide a readily available, off-the-shelf conduit for CABG. Here we evaluate the use of small diameter HAV for CABG in a non-human primate model. Methods: Adult male baboons (n=7; 26.8 - 37.0 kg) were imaged by left heart catheterization and computed tomography angiography. CABG was performed using a 3.5 mm diameter HAV to the left anterior descending (LAD) or right coronary artery (RCA) via sternotomy with cardiopulmonary bypass. The proximal coronary artery was ligated to prevent competitive flow and graft transit time flowmetry (TTFM) was assessed after implant. Angiography at 2 weeks, 1, 3, and 6 months evaluated graft patency and heart function. HAVs explanted at 6 months were assessed by immunohistochemistry for host cellular response and remodeling. Results and Conclusion: Baboons underwent CABG using a 3.5 mm HAV from the ascending aorta to the LAD (n=2) or RCA (n=5). The diminutive LAD led to early graft loss due to size mismatch and poor runoff. HAV bypass to the dominant RCA (TTFM: 22 ± 7.7 mL/min) resulted in sustained graft patency for up to 6 months post-implantation. HAV explant histology revealed infiltration of multiple host cell populations with formation of a neoadventitial layer and evidence of luminal endothelization. HAV conduits retained structural integrity with no evidence of mechanical failure throughout the study. These results demonstrate that tissue-engineered HAVs may provide an off-the-shelf conduit for CABG.
Variability of the single-breath carbon monoxide transfer factor as a function of inspired oxygen pressure
Authors: RO Crapo, RE Kanner, RL Jensen, CG Elliott
Journal: European Respiratory Journal (1988)

We measured single-breath CO transfer factor (TLCO) and alveolar oxygen partial pressure (PAO2) six times at each of three fractions of inspired oxygen (FIO2) (0.17, 0.21, 0.26) in twelve healthy subjects, to determine whether one FIO2 would have the advantage of producing less variable TLCO results than the others. Measured TLCO was adjusted for the increase in carboxyhaemoglobin during the tests. We found no significant differences in intra- or interindividual variance as a function of test FIO2.
Abstract P1102: Rna-seq Analyses Reveal Roles Of The Hvcn1 Proton Channel In Cardiac Ph Homeostasis
Authors: Xin Wu, Yawei Li, Mark Maienschein-Cline, Leonid Feferman, Longjun Wu, Liang Hong
Journal: Circulation Research (2022)

Introduction: The voltage-gated proton channel Hv1 is a member of the voltage-gated ion channel family. Hv1 channel controls acid extrusion and regulates pH homeostasis in various cell types. Recent evidence showed that the Hv1 were expressed in the heart. Hypothesis: We propose the Hv1 channel is associated with cardiac function. Methods: To investigate the role of Hv1 in cardiac myocytes, we performed a transcriptomic analysis of wild-type (WT) and Hv1-/- mouse hearts. Results: Hv1 null hearts exhibited a differential transcriptome profile compared with wild-type hearts. The RNA-seq data indicating impaired pH homeostasis in Hv1 null hearts were the downregulated NADPH oxidoreductases (NOXs) and decreased expression of Cl-/HCO3- exchanger. Additionally, Hv1 null hearts exhibited differential expression of cardiac ion channels, suggesting a potential role of Hv1 in cardiac electrophysiological remodeling. Conclusions: The data indicated that Hv1 was involved in cardiac pH homeostasis and showed that Hv1 was a regulator of gene transcriptional networks controlling NOX signaling and CO2 homeostasis in the heart. The study highlights the importance of Hv1 in cardiac function and may present a new target associated with heart diseases.
Abstract P3066: Macrophage-derived Ccl24 Worsens Cardiac Dysfunction Following Pressure-overload
Authors: Preethy Parthiban, Fanta Barrow, Dogacan Yucel, Richard Gonigam, Adam Herman, Hailey Rhoades, Maya Demirchian, Haiguang Wang, Jop H Van Berlo, Xavier Revelo
Journal: Circulation Research (2022)

Heart failure (HF) is the leading cause of death worldwide. Systemic inflammation is associated with HF and is considered an independent predictor of adverse cardiac outcomes. Macrophages are the most abundant immune cells in the heart and have integral roles in cardiac homeostasis and remodeling. Despite their unique identity and homeostatic functions, the precise role of cardiac macrophages during cardiac remodeling is poorly understood. We have previously reported that cardiac resident macrophages expand early in response to pressure overload injury and provide cardioprotection. Using single-cell mRNA sequencing, we revealed that these macrophages consist of distinct subsets including a population that highly expresses C-C Motif Chemokine Ligand 24 (CCL24). CCL24 is a chemokine that promotes immune cell trafficking and activation through its receptor expressed on immune cells, fibroblasts, and cardiomyocytes. Here, we tested whether CCL24 regulates cardiac adaptation to pressure overload by performing transverse aortic constriction (TAC) in whole-body CCL24 knockout (CCL24KO) mice. Aortic constriction during TAC increases the pressure overload in ventricular chambers leading to an early compensated hypertrophy and diastolic dysfunction followed by systolic dysfunction and decompensated heart failure. Despite no differences at steady state, CCL24KO mice showed an improved cardiac function after TAC-induced pressure overload. Compared with WT controls, CCL24KO mice had a higher ejection fraction and fractional shortening. Furthermore, CCL24KO mice had increased hypertrophy but improved diastolic function. These results suggest that CCL24 worsens cardiac dysfunction leading to decompensated HF in response to pressure overload. Interestingly, CCL24KO mice have higher proportions of neutrophils and eosinophils at steady state, suggesting that the presence of these cells may facilitate cardiac repair. Overall, our findings indicate that macrophage-derived CCL24 is detrimental to cardiac function in response to pressure overload injury. The results of this study uncover CCL24 as a central mechanism by which cardiac resident macrophages promote cardiac inflammation and HF.
Abstract P1063: Investigation Of Synthetic Membrane-stabilizing Copolymers To Dystrophin-deficient Skeletal Muscle Fibers
Authors: Dongwoo Hahn, Adelyn Crabtree, Timothy Lodge, Benjamin Hackel, Frank Bates, Joseph M Metzger
Journal: Circulation Research (2022)

Duchenne muscular dystrophy (DMD) occurs by the lack of cytoskeletal protein dystrophin which is essential for the preservation of structural integrity of the muscle cell membrane. DMD develops severe skeletal muscle weakness, degeneration, and early death. We applied amphiphilic synthetic membrane stabilizers to the mdx skeletal muscle (flexor digitorum brevis; FDB) to compare the effectiveness in restoring contractile function in dystrophin-deficient muscle. After isolating the FDB fibers by enzymatic digestion and trituration from twenty-six adult male mice (5 C57/BL10, 21 mdx; at least 15 fibers/animal), we plated them on laminin-coated coverslip and treated them with poloxamer 188 (PEO 75 -PPO 30 -PEO 75 ; 8,600 g/mol; P188), architecturally reversed (PPO 15 -PEO 200 -PPO 15 , 10,700 g/mol), and diblock (PEO 75 -PPO 15 -C 4 , 4,200 g/mol) copolymers in 15 and 150 μM at 25 o C for 10 min. We assessed the twitch kinetics of sarcomere length (SL) and intracellular Ca 2+ transient by Fura-2, AM in field stimulation (25 V, 0.2 Hz, 25 o C). Twitch peak SL shortening of mdx FDB fibers was depressed to 30% of the dystrophin-replete control FDB fibers from BL10 (P &lt; 0.001). Treatment of mdx single FDB fibers with copolymers rapidly restored the twitch peak SL shortening by over 60%, especially P188 at 15 μM (60% of BL10 FDB, P &lt; 0.001) and 150 μM (90% of BL10 FDB, P &lt; 0.001). Twitch peak Ca 2+ transient from mdx FDB fibers was depressed by 50% compared to BL10 FDB fibers (P &lt; 0.001). Interestingly, acute copolymer treatment of mdx FDB fibers significantly increased the twitch peak Ca 2+ transient by 20-45%, especially P188 at 150 μM up to 75% of the BL10 FDB fibers (P = 0.472). Our data shows that the structure and concentration of the synthetic copolymers lead to different effectiveness on rescuing the twitch contractile function and Ca 2+ handling in dystrophin-deficient skeletal muscle fibers. Notably, acute treatment for 10 min with copolymers (P188, 150 μM) elicited over 3-fold improvement of peak SL shortening in mdx isolated skeletal muscle fibers. This study highlights copolymers as effective membrane stabilizing molecules in the restoration of dystrophin-deficient skeletal muscle function and the importance of copolymer structure, molecular weight, and concentration.
Abstract P1023: Single-Cell Metabolic Reconstruction Predicts Regenerative Capacity In Cardiomyocytes
Authors: Kristy Wang, Marcus Alexander, Jack Goodman
Journal: Circulation Research (2022)

Background: Adult mammalian hearts have limited regenerative capacity following ischemic injury, whereas neonatal hearts can fully regenerate. Uncovering the mechanisms underlying this ability could identify potential avenues for treatment following cardiac injuries. There has been evidence that changes in the tricarboxylic acid (TCA) cycle are involved in transition of cells out of a pluripotent state. Our hypothesis is that a specific metabolic profile will be associated with regenerative capacity in cardiomyocytes (CMs), and our subsequent goal is to characterize its activity. Methods: Previously published single-cell RNA-Seq data (GSE130699, GSE153481) from mouse hearts subjected to ischemic or sham injury at neonatal (P1) or adult (P8) stages (10987 CMs) were used to calculate metabolic reaction activity scores (RAS), which assign activity to each reaction based on gene expression (Damiani et al, 2020). We then used enrichment analysis to compare metabolic changes between experimental conditions. CMs were clustered into metabolic clusters based on RAS and compared to clusters based on total gene expression. We identified the metabolic reactions that are the best predictors of regenerative ability using LASSO regularization logistic regression. Results: Significant (p ≤ .05) differences in metabolism were identified between neonatal and adult CMs. Clustering based on RAS revealed four distinct metabolic profiles in neonatal CMs, but only two (regenerative and non-regenerative) in adult CMs. Compared to other CM clusters, regenerative CMs exhibited significantly upregulated TCA, nucleic acid, and folate metabolism. This subpopulation was enriched in the neonatal condition, resulting in the significant differences seen in overall CM metabolism between conditions. Further, regression using metabolic activity allowed us to predict the regenerative subpopulation of CMs with greater than 85% accuracy. Conclusion: In conclusion, we characterize the unique metabolic profiles of CMs that can be used to identify the regenerative subpopulation of CMs. This suggests that the different metabolic profile seen in regenerative CMs may play a significant role in their regenerative capacity and their differentiation to non-regenerative CMs.
Abstract P2120: Microdystrophin Design Comparisons In Dystrophin-Deficient Cardiomyocytes
Authors: Asuka Eguchi, Adriana Fernanda Gonzalez, Sofia Torres-Bigio, Sriram Bhimaraju, Foster Birnbaum, Helen M Blau
Journal: Circulation Research (2022)

Duchenne muscular dystrophy (DMD) is a severe muscle wasting disease caused by the lack of dystrophin. Dilated cardiomyopathy is the leading cause of death in DMD patients. Preclinical data show that smaller versions of dystrophin, called microdystrophins, can ameliorate disease progression. These transgenes, amenable to packaging into adeno-associated virus, have shown to be effective in improving skeletal muscle function; however, the functional benefit of microdystrophins in delaying heart failure is unknown. To identify the design principles that are important for addressing DMD heart dysfunction, three microdystrophin variants currently in clinical trials were tested in cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) with deficiencies in dystrophin. Previously, we reported that mechanical contraction and calcium handling are impaired in DMD iPSC-CMs. To test the functional benefit of the microdystrophins, we performed traction force microscopy, that provides multiparametric measurements of contraction, and calcium imaging with a ratiometric calcium-binding dye. Our results show a partial rescue of contractile deficits and aberrant calcium handling, underscoring the need for new design variants that address cardiomyocyte dysfunction.
The daily variability of bronchial responsiveness to methacholine
Authors: CJ Trigg, N Jhalli, MJ Herdman, DR Cundell, JM Thomas, RJ Davies
Journal: European Respiratory Journal (1990)

Ten mild atopic asthmatics on inhaled beta 2-agonists alone were studied in order to determine the repeatability of methacholine inhalation provocation tests at 24 h intervals over a period of 5 days. Such patients are most frequently studied in therapeutic trials of anti-asthmatic medications. There were no significant differences in results obtained on any of the days and no evidence for the development of tolerance to methacholine in this group of patients at one day intervals. The 95% confidence interval for repeatability of the results was +/- 1.05 doubling doses of methacholine, and 95% range +/- 2.36 doubling doses, comparable to the results obtained by other investigators on similar patients. Some investigators have produced more highly repeatable results but these have generally been obtained using highly selected groups of patients.
Near-fatal asthma
Authors: NA Molfino, AS Slutsky
Journal: European Respiratory Journal (1994)

The prevalence of patients with acute severe asthma appears to be increasing in many countries. In the present review, we summarize data in the literature relating to the prevention and treatment of fatality-prone asthmatics. The underlying assumption is that increased understanding of near-fatal asthma will increase our understanding of the pathophysiology of severe asthma, and lead to interventions that could reduce the mortality rate from asthma. Recognition of acute life-threatening asthma attacks by any physician is mandatory, since lack of such diagnosis and appropriate treatment has been shown to have devastating consequences. The characteristics that allow identification of asthmatics prone to die in ambulatory settings (i.e. previous admissions, type of therapy, etc.) as well as the principal precipitating factors of acute near-fatal and fatal attacks of asthma are reviewed. Predisposing factors, such as lack of appropriate treatment, lack of compliance or poor preventive measures are debated. Finally, we discuss current therapeutic approaches in emergency facilities, based on the major pathophysiological findings in near-fatal asthma.
Abstract P1133: Association Of Mesenchymal Stem Cells Therapy And An Agonist Of Adenosine Receptor On Monocrotaline-induced Pulmonary Arterial Hypertension In Rats
Authors: Bruno Dematté, Jaqueline S Da Silva, Juliana F Vasques, Bruna Rocha, Tadeu Montagnoli, Bianca Nascimento-Carlos, Rodolfo Maia, Eliezer Barreiro, Rosalia Mendez-Otero, Gisele Zapata-Sudo
Journal: Circulation Research (2022)

Introduction: Pulmonary arterial hypertension (PAH) is characterized by an intense inflammatory component leading to vascular remodeling, increasing the pulmonary artery pressure, eventually resulting in right ventricular dysfunction. Hypothesis: Association of human mesenchymal stem cells (hMSC) therapy and LASSBio-1860 (agonist of adenosine receptors) would reduce the inflammatory response and vascular remodeling, decreasing the vascular resistance and pulmonary artery pressure, improving right ventricle function and reducing hypertrophy. Methods: Protocols were approved by Animal Care and Use Committee at Universidade Federal do Rio de Janeiro. PAH was induced in male Wistar rats by injection of monocrotaline (MCT; 60 mg/kg, i.p.) and confirmed within 14 days by transthoracic echocardiography. Groups were orally treated daily during 14 days with vehicle, LASSBio-1860 (180 μmol/kg) after a single intravenous injection of 10 5 hMSC At the end of protocol, tissues were collected and processed to evaluate expression of proteins using immunohistochemical and western-blotting analysis. Results: Mean pulmonary artery acceleration time (PAAT) was reduced in MCT-induced PAH group compared to the control group from 31.0 ± 1.5 to 21.9 ± 1.3 ms. In contrast, the association of LASSBio-1860 and hMSC has recovered the PAAT to 31.0 ± 2.0 ms, which effect was not observed in isolated treatment either with LASSBio-1860 or hMSC (23.5 ± 2.1 and 22.2 ± 2.2 ms). Table 1 shows hemodynamic, molecular and immunohistochemical parameters. In conclusion, the association of LASSBio-1860 and hMSC improved hemodynamic, morphologic and inflammatory parameters in an MCT-induced model of PAH.
Abstract P1108: Functional Genomics Analysis Of Sox17 Locus To Define The Pathogenic Role Of FUBP1 In Pulmonary Arterial Hypertension
Authors: Wei Sun, Danli Jiang, Gang Li, Stephen Y Chan
Journal: Circulation Research (2022)

Rationale: Pulmonary arterial hypertension (PAH) is an enigmatic and morbid disease where insights are emerging regarding genetic susceptibility. Genome-wide Association Studies (GWAS) have identified SOX17 as the most significant PAH-associated genomic locus. The allele of tag SNP in this locus is associated with 1.8-fold higher PAH risk. It has been challenging to define the mechanisms underlying the contribution of the PAH-associated functional SNPs (fSNPs) to pathogenesis of the disease. Methods: We developed a post-GWAS functional genomics strategy to define the causative fSNPs and identify the associated biological mechanisms. This analysis includes Reel-seq (Regulatory element-sequencing), an EMSA-based high-throughput technique to identify fSNPs in a synthetic DNA library containing PAH-associated SNPs; SDCP-MS (SNP-specific DNA competition pulldown-mass spectrometry) to identify proteins that specifically bind to fSNPs; and AIDP-Wb (allele-imbalanced DNA pulldown-Western blot) to show allele-imbalanced binding of these proteins to fSNPs. The regulation of risk gene expression by these fSNP-binding proteins and their pathogenicity were determined in human pulmonary arterial endothelial cells (PAECs) and confirmed in PAH animal models and patients. Results: By using high-throughput Reel-seq and subsequent validation with EMSA, intergenic SNP rs4738801 in SOX17 locus was identified as a fSNP from a library containing 254 PAH-associated haplotype SNPs. This fSNP resides in a remote upstream enhancer region of SOX17, an endothelial effector increasingly associated with PAH pathogenesis. Using SDCP-MS and AIDP-Wb, we found that the transcription factor FUBP1 binds to rs4738801 risk allele C with lower affinity than non-risk allele G, resulting in a decrease in SOX17 expression. FUBP1 and target gene SOX17 controlled PAH-associated pathophenotypes in PAECs, including proliferation, apoptosis, and angiogenesis. Downregulated by the major acquired PAH trigger hypoxia, FUBP1 and SOX17 were decreased in lungs and pulmonary ECs isolated from PAH patients and mouse models. A 3.77-fold enrichment of fSNP rs4738801 risk allele C was found in patients with PAH induced by hypoxia, but not in PAH associated with connective tissue disease or congenital heart disease. Conclusions: FUBP1 controls SOX17 expression via allele-specific binding to PAH-associated fSNP rs4738801. The reduced binding of FUBP1 to risk allele C defines the genomic architecture contributing to the SOX17-dependent genetic susceptibility of PAH. The downregulation of FUBP1-SOX17 by hypoxia results in endothelial dysfunction, contributing to the acquired pathogenesis of PAH. These findings identify a novel role of FUBP1 in the functional regulation of SOX17 locus and elucidating a pathogenic mechanism that combines the acquired PAH-triggering factors and altered genetic susceptibility.